September 22, 2008 (Montreal, Quebec) — In a trial of patients with primary progressive multiple sclerosis (PPMS), rituximab (Rituxan, Biogen Idec/Genentech) appeared to have efficacy only in younger patients with signs of inflammation, suggesting that parameters such as age and magnetic resonance imaging (MRI) findings might be more useful for directing therapy than clinical designations.

The main results of the trial, though, showed no statistical difference in the time to confirmed disease progression with rituximab vs placebo in this patient group.

The research was presented here at the World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS). The study was led and presented by Kathleen Hawker, MD, an associate professor in the department of neurology at Ohio State University, in Columbus.

B cells are known to play a pathogenic role in MS. Rituximab is a chimeric monoclonal antibody that selectively depletes CD20-positive B cells. It has shown promise against MS in phase 1 and 2 trials.

In the phase 2/3 double-blind trial presented here, 439 patients with PPMS were randomized in a 2:1 ratio to receive two 1000 mg injections of rituximab, spaced 2 weeks apart, every 24 weeks, for a total of 8 doses (the last of which was given at 74 weeks) or placebo. Patients were followed up for 96 weeks in the efficacy analysis and 122 weeks in the safety analysis. This is the longest course of rituximab ever given to MS patients.

Participants in the trial all had an Expanded Disability Status score between 2 and 6.5. Most were between the 40 and 64 years old, with an average age of about 50 years. Approximately 35% had undergone previous immunomodulatory therapy, and there was a washout period to account for that exposure. At baseline, about 25% of patients had at least 1 gadolinium (GD)-positive lesion.

Overall, 85% of patients on placebo and 82.5% on rituximab remained on therapy for the duration of the trial. Rituximab-treated patients experienced far more injection-site reactions, particularly at the first dose, than those on placebo.They also had a slightly higher rate of serious infections, occurring in 4.5% of rituximab vs less than 1.0% of placebo patients.

In an intent-to-treat analysis, confirmed disease progression (CDP) at 96 weeks was 30.2% with rituximab and 38.5% with placebo (= .1442, nonsignificant). Although brain-volume changes remained the same in both groups, the median T2-lesion volume at 96 weeks was significantly lower in rituximab-treated patients (P = .0008).

Subgroup analyses revealed that younger patients with signs of inflammation, as evidenced by the presence of GD-positive lesions, responded best to rituximab. Among those under the age of 51 years, CDP at 96 weeks was 27.5% with rituximab and 45% with placebo (P = .0101). In those with at least 1 GD-positive lesion, CDP was 27% with rituximab and 53% with placebo (P = .0069). In patients who were both under 51 years and had at least 1 GD-positive lesion, CDP was 24% with rituximab and 52% with placebo (P = .0088). CDP findings were even significant for patients under 55 years with GD-positive lesions (29% vs 50%; P = .0126).

Wait for Better Patient Selection

"We saw encouraging results with rituximab in relapsing remitting MS, so it was very interesting to see what the outcome would be in primary progressive [PPMS], because almost all drugs that work for relapsing remitting don't work for primary progressive," Askel Siva, MD, a professor of neurology at Istanbul University Cerrahpasa School of Medicine, in Turkey, told Medscape Neurology & Neurosurgery. Dr. Siva moderated the session in which the findings were presented.

Based on these results, though, "I don't feel that we should go farther with rituximab at the moment in primary progressive [MS], especially with the risk of late side effects," said Dr. Siva. He added, however, that in the future, as it becomes possible to better identify who might respond to rituximab, the treatment should be reconsidered.

"This seems to be another negative study in [PPMS]," Dr. Siva said, but both he and Dr. Hawker agreed that these findings call into question the use of clinical designations to select therapy for MS patients. "There was more than expected MRI activity in this study group with [PPMS], so maybe the question is: Are all primary progressive MS cases really primary progressive, in general?" Dr. Siva said.

"There were very few relapses in our trial, so by our clinical designation, this is primary progressive," said Dr. Hawker. "I think our problem is that people with different immunobiologies have different courses of the disease, and age may be [another] factor [affecting] how the immune system responds."

As for better patient selection, Dr. Hawker thinks it may soon be possible. "I think the parameters of [being] younger, [having] more inflammatory [signs], and [being] earlier on [in the disease course] may pick out patients who are amenable to treatment [with rituximab]." The next step, she said, is to conduct new rituximab trials focusing on patients such as these.

Dr. Hawker has been a consultant for Genentech/Biogen Idec, and a speaker for Teva, Bayer, and Biogen Idec. This study was funded by and conducted in collaboration with Genentech.

World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS): Abstract 78. Presented September 20, 2008.

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